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Cited by 549

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

A Molecular Basis for Insulin Resistance

Open access
Paz, Keren, Hemi, Rina, LeRoith, Derek, Karasik, Avraham, Elhanany, Eytan, Kanety, Hannah, Zick, Yehiel·1997·Journal of Biological Chemistry
DOI 10.1074/jbc.272.47.29911
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Abstract

Tumor necrosis factor alpha (TNFalpha) or chronic hyperinsulinemia that induce insulin resistance trigger increased Ser/Thr phosphorylation of the insulin receptor (IR) and of its major insulin receptor substrates, IRS-1 and IRS-2. To unravel the molecular basis for this uncoupling in insulin signaling, we undertook to study the interaction of Ser/Thr-phosphorylated IRS-1 and IRS-2 with the insulin receptor. We could demonstrate that, similar to IRS-1, IRS-2 also interacts with the juxtamembrane (JM) domain (amino acids 943-984) but not with the carboxyl-terminal region (amino acids 1245-1331) of IR expressed in bacteria as His6 fusion peptides. Moreover, incubation of rat hepatoma Fao cells with TNFalpha, bacterial sphingomyelinase, or other Ser(P)/Thr(P)-elevating agents reduced insulin-induced Tyr phosphorylation of IRS-1 and IRS-2, markedly elevated their Ser(P)/Thr(P) levels, and significantly reduced their ability to interact with the JM region of IR. Withdrawal of TNFalpha for periods as short as 30 min reversed its inhibitory effects on IR-IRS interactions. Similar inhibitory effects were obtained when Fao cells were subjected to prolonged (20-60 min) pretreatment with insulin. Incubation of the cell extracts with alkaline phosphatase reversed the inhibitory effects of insulin. These findings suggest that insulin resistance is associated with enhanced Ser/Thr phosphorylation of IRS-1 and IRS-2, which impairs their interaction with the JM region of IR. Such impaired interactions abolish the ability of IRS-1 and IRS-2 to undergo insulin-induced Tyr phosphorylation and further propagate the insulin receptor signal. Moreover, the reversibility of the TNFalpha effects and the ability to mimic its action by exogenously added sphingomyelinase argue against the involvement of a proteolytic cascade in mediating the acute inhibitory effects of TNFalpha on insulin action.

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Metadata

Authors
Paz, K., Hemi, R., LeRoith, D., Karasik, A., Elhanany, E., Kanety, H., & Zick, Y.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1997-11
Volume
272
Issue
47
Pages
29911-29918
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.272.47.29911
OpenAlex
W2003659422
Cited by
549
References
4
FWCI
5.63
Type
journal article
Language
en
Open access
hybrid

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